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Endpoints definition

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ISSN: 2471-9919
Evidence Based Medicine and
Practice
Roever, Evidence Based Medicine and Practice 2016, 1:2
DOI: 10.4172/ebmp.1000e111
Editorial
EBMP
Endpoints in Clinical Trials: Advantages and Limitations
Leonardo Roever*
Department of Clinical Research, Federal University of Uberlândia, Uberlândia, Brazil
*Corresponding author: Roever L, Department of Clinical Research, Av Pará, 1720-Bairro Umuarama, Uberlândia-MG-CEP 38400-902, Brazil, Tel: +553488039878; Email: leonardoroever@hotmail.com
Rec Date: 11 December, 2015; Acc Date: 18 December, 2015; Pub Date: 25 December, 2015
Copyright: © 2016 Roever L. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Introduction
Primary endpoints in clinical trials must meet 3 criteria:
A) Clinically relevant
B) Sensitive to treatment effect
C) Measurable and interpretable. Secondary endpoints could
provide a more global view of the benefit of the treatment being tested
and by clarifying its risk-to-benefit ratio; may be of 2 types: A) Those
that, like primary endpoints, are clinically relevant and may be taken
into consideration for drug indications; and B) “Feel-good” endpoints,
which are not likely to lead to a new indication or a change in labelling
but might provide reassurance about the primary endpoint along with
new information about the disease. Some secondary endpoints might
be exploratory analyses, although they might demonstrate biologically
plausible effects, they remain hypothesis-generating and will need to
be confirmed by additional studies. Table 1 and 2 shows the terms and
definitions used in the outcomes of clinical trials [1-4].
Term
Definition
Biomarker (biological marker)
A characteristic that is measured and evaluated objectively as an indicator of normal biologic processes,
pathogenic processes, or pharmacologic responses to a therapeutic intervention.
Clinical end point
A characteristic or variable that reflects how a patient feels or functions or how long a patient survives.
Surrogate end point
A biomarker that is intended to substitute for a clinical end point, i.e., a biomarker that is expected to predict
clinical benefit, harm, or lack of benefit or harm.
Intermediate end point
A characteristic that is intermediate in the causal pathway between an intervention and the clinical end point.
Table 1: Shows the outcomes in major clinical trials.
Endpoints
Definition
Advantages
Limitations
Overall Survival (OS)
Time from randomization* until death
from any cause
Universally accepted measure of direct
benefit
Easily and precisely measured
May require a larger trial population and longer followup to show statistical difference between groups
May be affected by crossover or subsequent therapies
Includes deaths unrelated to disease
Progression-Free
Survival (PFS)
Time from randomization* until disease
progression or death
Time to Progression
(TTP)
Time from randomization* until objective
disease progression; does not include
deaths
Requires small sample size and shorter
follow-up time compared with OS
Includes measurement of stable disease
(SD)
Not affected by crossover or subsequent
therapies
Generally based on objective and
quantitative assessment
Validation as a surrogate for survival can be difficult in
some treatment settings
Not precisely measured (i.e., measurement may be
subject to bias)
Definition may vary among trials
Requires frequent radiologic or other assessments
Requires balanced timing of assessment among
treatment arms
Time to Treatment
Failure (TTF)
Time from randomization* until objective
disease progression; does not include
deaths.
Useful in settings in which toxicity is
potentially as serious as disease
progression (e.g., allogeneic stem cell
transplant)
Does not adequately distinguish efficacy from other
variables, such as toxicity
Time to Next
Treatment (TTNT)
Time from end of primary treatment to
institution of next therapy
For incurable diseases, may provide an
endpoint meaningful to patients
Not commonly used as a primary endpointSubject to
variability in practice patterns
Event-Free Survival
(EPS)
Time from randomization* to disease
progression, death, or discontinuation of
treatment for any reason (e.g. toxicity,
patient preference, or initiation, of a new
treatment without documented
progression)
Similar to PFS; may be useful in
evaluation of highly toxic therapies
Initiation of next therapy is subjective. Generally not
encouraged by regulatory agencies because it
combines efficacy, toxicity, and patient withdrawal
Time to Next
Treatment (TTNT)
Time from end of primary treatment to
institution of next therapy
For incurable diseases, may provide an
endpoint meaningful to patients
Not commonly used as a primary endpoint
Subject to variability in practice patterns
Evidence Based Medicine and Practice
ISSN:EBMP Evidence Based Medicine and Practice
Volume 1 • Issue 2 • 1000e111
Citation:
Roever L (2016) Endpoints in Clinical Trials: Advantages and Limitations. Evidence Based Medicine and Practice 1: e111. doi:
10.4172/ebmp.1000e111
Page 2 of 2
Overall response
rate (ORR)
Proportion of patients with reduction in
disease burden of a predefined amount
Duration of
Response (DoR)
Time from documentation of disease
response to disease progression
(Quality Of Life QOL) Symptoms
Reported by Patients
Toxicity
Other Common
Endpoints
Can be assessed in single-arm trials
Requires a smaller population and can be
assessed earlier compared with survival
trials
Effect is attributable directly to the drug,
not the natural history of the disease
Not a comprehensive measure of drug activity
Outcome self-reported by patients using
wellness scales, presence of adverse
effects and toxicity therapeutic
Patient perspective of direct clinical
benefit.
Reporting sometimes incomplete
Small symptoms and signs of difficult to assess Few
validated instruments Sometimes patients do not report
accurately the effects adverse
Rate of adverse effects
Definition of the benefit/risk balance of
therapy
Sometimes patients do not report accurately the effects
adverse
Response rate (RR) Response rate
measures disease size, usually using a
scan or X-ray.
Complete response (CR)
Disappearance of all clinical evidence of
disease.
Partial response (PR)
At least 30% reduction in size of all measureable
Stable disease (SD) or No change
(NC) Between a 30% reduction or <25%
increase in the size of all detectable
disease
Progressive disease (PD) Patients or
proportion of patients with a ≥ 25%
increase in size of disease since previous
measurement
Objective response rate (ORR) Percentage of patients
whose disease decreased (Partial response – PR)
and/or disappears (Complete response – CR) after
treatment.
Disease control rate (DCR) or clinical
benefit rate (CBR) Percentage of
patients whose disease shrinks or
remains stable over a certain time
period. DCR is the sum of the complete,
partial and stable disease rates.
Duration of response (DR) Time from
confirmation of a partial response (PR),
complete response (CR) or stable
disease (SD), until the disease has been
shown to progress following treatment
(progressive disease or PD).
Performance status (PS) Measure of how well a
patient with a disease diagnosis can perform ordinary
tasks in daily life before, during or after treatment.
Specific numeric PS scales indicate levels of disability
due to disease, and/or severity of symptoms. Two main
scales are.
Table 2: Outcomes in major clinical trials. *Not all trials are randomized. In nonrandomized trials, time from study enrolment is commonly used.
References
3. http://www.biooncology.com/clinical-trials/clinical-endpoints/advantages-
1. Evans S (2007) When and How Can Endpoints Be Changed after Initiation
4. http://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf
of a Randomized Clinical Trial. PLOS Clin Trial 2: e18.
limitations
2. Vaz-carneiro A, Luz R, Borges M, Costa J (2014) Primary and Secondary
Outcomes in Oncology Clinical Trials: Definitions and Uses. Acta Med Port
27: 498-502
Evidence Based Medicine and Practice
ISSN:EBMP Evidence Based Medicine and Practice
Volume 1 • Issue 2 • 1000e111
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